The fetal mortality rate in pregnancies with severe intrauterine growth restriction (IUGR) and preeclampsia (PE) approaches 50%. In this competitive renewal application, we propose experiments to elucidate the mechanisms through which inflammation promotes irreversible placental damage in these pregnacies which result in a life-threatening reduction in the the flow of nutrients from mother to fetus. Our preliminary results show that hypoxia-reperfusion injury likely triggers an interleukin-1 (IL-1)-[unreadable]-driven inflammatory cascade in placental villus core fibroblasts (FIBs) in pregnancies with IUGR and PE. Importantly, we observed that treatment with glucocorticoid (GC), and the pineal gland peptide melatonin (MT), suppressed IL-[unreadable] effects on cytokine expression in FIBs. It is our working hypothesis that ROS promote placental damage in IUGR and PE through an inflammatory cytokine response in the core of the placenta that accompanies and/or precedes damage to the syncytium. A corollary to this hypothesis is that these deleterious pathways can be suppressed by treatment with GC and MT. Our Specific Aims are: 1) to test the hypothesis that GC and MT treatment effectively suppresses an IL-[unreadable]-driven inflammatory cytokine cascade in core FIBs; 2) to determine whether GC and MT treatment suppress a reactive oxygen species (ROS)-driven inflammtory response using placental perfusion methodology; and 3) To identify novel pathways of placental pathophysiology in pregnancies with IUGR and PE. For studies, we will couple physiologically relevant in vitro techniques of primary cell culture and dual (maternal + fetal) placental perfusion with state of the art molecular methodologies including laser capture microdissection (LCMD) and real-time quantitative PCR (qRTPCR). Not only is severe IUGR a major cause of fetal mortality, but surivivng fetuses are at risk for cardiovascular disease and diabetes as adults. Our proposed studies will provide insight into the pathogenesis of placenta damage in IUGR and PE, test potential therapeutic interventions, and elucidate novel markers in these major complications of pregnancy.